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- PDB-9r9m: Crystal Structure of human MLH1 C-terminal domain with cyclic pep... -

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Basic information

Entry
Database: PDB / ID: 9r9m
TitleCrystal Structure of human MLH1 C-terminal domain with cyclic peptide (2S)-N-[(6S,9S,12S,15S,18S,26aR)-12-(4-aminobutyl)-18-benzyl-21-(2-carbamoylethyl)-9-(hydroxymethyl)- 15-[(4-hydroxyphenyl)methyl]-1,7,10,13,16,19,22-heptaoxo-hexacosahydropyrrolo[2,1-c]1,4,7,10,13,16,19-heptaazacyclotetracosan-6-yl]-2-[(2S)-2-acetamidopropanamido]-3-methylbutanamide
Components
  • (Cyclic peptide ...) x 2
  • DNA mismatch repair protein Mlh1
KeywordsDNA BINDING PROTEIN / MutL / DNA repair / endonuclease
Function / homology
Function and homology information


chiasma / late recombination nodule / male meiosis chromosome segregation / meiotic metaphase I homologous chromosome alignment / Defective Mismatch Repair Associated With MLH1 / Defective Mismatch Repair Associated With PMS2 / negative regulation of mitotic recombination / MutLalpha complex / meiotic spindle midzone assembly / guanine/thymine mispair binding ...chiasma / late recombination nodule / male meiosis chromosome segregation / meiotic metaphase I homologous chromosome alignment / Defective Mismatch Repair Associated With MLH1 / Defective Mismatch Repair Associated With PMS2 / negative regulation of mitotic recombination / MutLalpha complex / meiotic spindle midzone assembly / guanine/thymine mispair binding / meiotic telomere clustering / nuclear-transcribed mRNA poly(A) tail shortening / positive regulation of isotype switching to IgA isotypes / homologous chromosome pairing at meiosis / resolution of meiotic recombination intermediates / positive regulation of isotype switching to IgG isotypes / female meiosis chromosome segregation / synaptonemal complex / isotype switching / Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta) / Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha) / ATP-dependent DNA damage sensor activity / oogenesis / mismatch repair / somatic hypermutation of immunoglobulin genes / male germ cell nucleus / response to bacterium / TP53 Regulates Transcription of DNA Repair Genes / double-strand break repair via nonhomologous end joining / Meiotic recombination / intrinsic apoptotic signaling pathway in response to DNA damage / enzyme activator activity / chromosome / spermatogenesis / chromatin binding / enzyme binding / ATP hydrolysis activity / nucleoplasm / ATP binding / membrane / nucleus
Similarity search - Function
DNA mismatch repair protein Mlh1, C-terminal / DNA mismatch repair protein Mlh1 C-terminus / DNA mismatch repair protein family, N-terminal / DNA mismatch repair protein, S5 domain 2-like / DNA mismatch repair, conserved site / DNA mismatch repair protein MutL/Mlh/Pms / DNA mismatch repair protein, C-terminal domain / DNA mismatch repair proteins mutL / hexB / PMS1 signature. / DNA mismatch repair protein, C-terminal domain / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase ...DNA mismatch repair protein Mlh1, C-terminal / DNA mismatch repair protein Mlh1 C-terminus / DNA mismatch repair protein family, N-terminal / DNA mismatch repair protein, S5 domain 2-like / DNA mismatch repair, conserved site / DNA mismatch repair protein MutL/Mlh/Pms / DNA mismatch repair protein, C-terminal domain / DNA mismatch repair proteins mutL / hexB / PMS1 signature. / DNA mismatch repair protein, C-terminal domain / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / Histidine kinase/HSP90-like ATPase superfamily / Ribosomal protein S5 domain 2-type fold, subgroup / Ribosomal protein S5 domain 2-type fold
Similarity search - Domain/homology
ACETATE ION / DNA mismatch repair protein Mlh1
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.281 Å
AuthorsThomsen, M. / Bandera, A.M. / Thieulin-Pardo, G.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Chemrxiv / Year: 2026
Title: Cyclic Peptide Inhibitors of the MLH1-MSH3 Interaction as a Potential Therapeutic Strategy for Huntington's Disease
Authors: Haque, T.S. / Orvieto, F. / Tomaselli, S. / Turcano, L. / De Simone, D. / Francone, A. / Micaelli, M. / Movetti, S. / Piacenti, V. / Gambini, L. / Alli, C. / Fodale, V. / Bianchi, E. / ...Authors: Haque, T.S. / Orvieto, F. / Tomaselli, S. / Turcano, L. / De Simone, D. / Francone, A. / Micaelli, M. / Movetti, S. / Piacenti, V. / Gambini, L. / Alli, C. / Fodale, V. / Bianchi, E. / Toniatti, C. / Kawahara, D. / Ghosh, S. / Koszelak-Rosenblum, M. / Zhu, G. / Kintzel, S. / Williams, D. / Larocque, J. / Thieulin-Pardo, G. / Thomsen, M. / Dominguez, C. / Iyer, R.R. / Finley, M. / Felsenfeld, D. / Boudet, J. / Monteagudo, E. / Vogt, T.F. / Prasad, B.C.
History
DepositionMay 20, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 8, 2026Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: DNA mismatch repair protein Mlh1
B: DNA mismatch repair protein Mlh1
I: Cyclic peptide 1
C: Cyclic peptide 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,36223
Polymers63,3244
Non-polymers1,03819
Water3,423190
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)125.302, 57.430, 118.007
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails (eV)
11A
21B

NCS domain segments:

Component-ID: 1 / Ens-ID: 1 / Beg auth comp-ID: THR / Beg label comp-ID: THR / End auth comp-ID: TYR / End label comp-ID: TYR / Auth seq-ID: 491 - 750 / Label seq-ID: 7 - 266

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

NCS ensembles : (Details: Local NCS retraints between domains: 1 2)

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein DNA mismatch repair protein Mlh1 / MutL protein homolog 1


Mass: 30607.809 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: C-terminal domain of MLH1 / Source: (gene. exp.) Homo sapiens (human) / Gene: MLH1, COCA2 / Production host: Escherichia coli (E. coli) / References: UniProt: P40692

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Cyclic peptide ... , 2 types, 2 molecules IC

#2: Protein/peptide Cyclic peptide 1


Mass: 1080.256 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#3: Protein/peptide Cyclic peptide 2


Mass: 1028.223 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Non-polymers , 4 types, 209 molecules

#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Ca
#6: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H3O2
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 190 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.37 Å3/Da / Density % sol: 63.49 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.25 / Details: 14% PEG 8K 200 mM Ca-Acetate 100 mM MES pH 6.25

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Jun 14, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.28→85.907 Å / Num. obs: 39599 / % possible obs: 100 % / Redundancy: 8.4 % / CC1/2: 0.9946 / Rmerge(I) obs: 0.09 / Rpim(I) all: 0.034 / Rrim(I) all: 0.096 / Net I/σ(I): 10.905
Reflection shellResolution: 2.281→2.321 Å / Redundancy: 8.03 % / Rmerge(I) obs: 1.412 / Num. unique obs: 1972 / CC1/2: 0.5268 / Rpim(I) all: 0.539 / Rrim(I) all: 1.515 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0430refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.281→85.907 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.949 / SU B: 5.722 / SU ML: 0.135 / Cross valid method: FREE R-VALUE / ESU R: 0.218 / ESU R Free: 0.178
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflectionSelection details
Rfree0.2202 2748 6.94 %Random selection
Rwork0.1953 36848 --
all0.197 ---
obs-39596 99.952 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 57.337 Å2
Baniso -1Baniso -2Baniso -3
1--0.315 Å20 Å20 Å2
2--1.968 Å2-0 Å2
3----1.653 Å2
Refinement stepCycle: LAST / Resolution: 2.281→85.907 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4075 0 132 190 4397
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0040.0124301
X-RAY DIFFRACTIONr_bond_other_d0.0050.0164081
X-RAY DIFFRACTIONr_angle_refined_deg1.2861.8715826
X-RAY DIFFRACTIONr_angle_other_deg0.5691.7819405
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3245503
X-RAY DIFFRACTIONr_dihedral_angle_2_deg0.342113
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.06810.229698
X-RAY DIFFRACTIONr_dihedral_angle_other_3_deg26.76204
X-RAY DIFFRACTIONr_dihedral_angle_6_deg13.78510.711197
X-RAY DIFFRACTIONr_dihedral_angle_other_6_deg16.173208
X-RAY DIFFRACTIONr_chiral_restr0.0670.2645
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.024901
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02945
X-RAY DIFFRACTIONr_nbd_refined0.1930.2740
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1660.23350
X-RAY DIFFRACTIONr_nbtor_refined0.1670.22027
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.070.22070
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1140.2162
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1850.29
X-RAY DIFFRACTIONr_nbd_other0.1620.256
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1120.25
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined0.0620.21
X-RAY DIFFRACTIONr_mcbond_it3.2195.8682011
X-RAY DIFFRACTIONr_mcbond_other3.2155.8622008
X-RAY DIFFRACTIONr_mcangle_it4.6910.5292511
X-RAY DIFFRACTIONr_mcangle_other4.69110.532512
X-RAY DIFFRACTIONr_scbond_it3.6326.2032290
X-RAY DIFFRACTIONr_scbond_other3.6316.2042291
X-RAY DIFFRACTIONr_scangle_it5.87611.2313315
X-RAY DIFFRACTIONr_scangle_other5.87511.2313316
X-RAY DIFFRACTIONr_lrange_it7.82957.0424605
X-RAY DIFFRACTIONr_lrange_other7.83556.8314573
X-RAY DIFFRACTIONr_ncsr_local_group_10.0290.053023
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)Weight position
11AX-RAY DIFFRACTIONLocal ncs0.028960.05
12BX-RAY DIFFRACTIONLocal ncs0.028960.05
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
2.281-2.340.3461660.30327030.30628780.9090.93399.68730.293
2.34-2.4040.2781840.28326280.28328120.9470.9461000.268
2.404-2.4740.3011840.26425500.26627340.9390.9561000.245
2.474-2.550.2521680.24424890.24526570.9630.9641000.218
2.55-2.6340.2391680.21224110.21425790.9640.9731000.19
2.634-2.7260.2621820.21223360.21525180.9570.9731000.189
2.726-2.8290.2341870.20322090.20523960.9650.9741000.179
2.829-2.9440.2231850.18521340.18823190.9670.9781000.167
2.944-3.0750.2131500.17821040.1822540.970.981000.165
3.075-3.2250.2411520.18819820.19221340.9580.9771000.18
3.225-3.3990.2661410.20319000.20720410.9650.9771000.198
3.399-3.6050.2281580.19517850.19719430.9740.9811000.195
3.605-3.8530.1881330.18817010.18818340.9810.9831000.195
3.853-4.1610.1891130.16715860.16816990.9820.9861000.183
4.161-4.5570.1731140.14214670.14415810.9840.9881000.172
4.557-5.0940.1851080.15113280.15414360.9810.9871000.19
5.094-5.8780.223880.20912000.2112880.9690.9771000.263
5.878-7.1910.252850.23610190.23811040.960.971000.294
7.191-10.1340.221500.1818220.1848720.970.981000.243
10.134-85.9070.226320.2594940.2575270.9630.94899.81020.354

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